ATM and ATR activities maintain replication fork integrity during SV40 chromatin replication.
ATM and ATR activities maintain replication fork integrity during SV40 chromatin replication.
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DOI：
10.1371/journal.ppat.1003283
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Fanning E
中科院分区：
文献类型：
--
作者：
Sowd GA;Li NY;Fanning E
DNA损伤检查点信号激酶共济失调毛细血管扩张突变（ATM）或ATM和Rad 3相关（ATR）的突变导致基因组不稳定性疾病。然而，目前尚不清楚这些综合征中观察到的不稳定性如何与DNA复制/修复缺陷和细胞周期检查点控制失败有关。作为一个简单的模型来解决这个问题，我们已经研究了在ATM和ATR活性抑制剂的存在下，在感染的细胞中的SV 40染色质复制。SV 40染色质复制产物的二维凝胶电泳和Southern印迹显示ATM活性阻止单向复制产物的积累，这意味着ATM促进复制相关双链断裂的修复。ATR活动在与停滞的分叉收敛时会导致功能性分叉的断裂。结果表明，在SV 40染色质复制过程中，内源性复制应激激活ATM和ATR信号传导，协调病毒复制中间体上的基因组维持机制的组装。所有的细胞都进化出了保持染色体中遗传信息完整性的途径。内源性和外源性试剂诱导DNA突变和其他损伤，最常见于DNA复制期间。这种DNA损伤受到一个复杂的蛋白质网络的监视，这些蛋白质相互作用以发出损伤信号，阻止DNA复制，并在复制恢复之前恢复基因组完整性。许多在哺乳动物宿主细胞的细胞核中复制的病毒已经进化为使这种监视系统失效或逃避，但是其他病毒，例如多瘤病毒如SV 40，激活它并以某种方式利用它来促进病毒后代的稳健复制。我们试图确定SV 40如何在感染细胞中诱导和部署宿主DNA损伤信号以促进病毒染色体复制。在这里，我们提出的证据表明，像宿主DNA，复制病毒DNA遭受损伤，激活监视和修复途径。与宿主复制不同，尽管有损伤信号，病毒DNA复制仍然存在，允许有缺陷的复制产物积累。在宿主DNA损伤信号传导的存在下，这些缺陷病毒产物吸引宿主损伤监测网络的蛋白质，其校正缺陷，从而使病毒繁殖最大化。
Mutation of DNA damage checkpoint signaling kinases ataxia telangiectasia-mutated (ATM) or ATM- and Rad3-related (ATR) results in genomic instability disorders. However, it is not well understood how the instability observed in these syndromes relates to DNA replication/repair defects and failed checkpoint control of cell cycling. As a simple model to address this question, we have studied SV40 chromatin replication in infected cells in the presence of inhibitors of ATM and ATR activities. Two-dimensional gel electrophoresis and southern blotting of SV40 chromatin replication products reveal that ATM activity prevents accumulation of unidirectional replication products, implying that ATM promotes repair of replication-associated double strand breaks. ATR activity alleviates breakage of a functional fork as it converges with a stalled fork. The results suggest that during SV40 chromatin replication, endogenous replication stress activates ATM and ATR signaling, orchestrating the assembly of genome maintenance machinery on viral replication intermediates. All cells have evolved pathways to maintain the integrity of the genetic information stored in their chromosomes. Endogenous and exogenous agents induce mutations and other damage in DNA, most frequently during DNA replication. Such DNA damage is under surveillance by a complex network of proteins that interact with one another to signal damage, arrest DNA replication, and restore genomic integrity before replication resumes. Many viruses that replicate in the nucleus of mammalian host cells have evolved to disable or evade this surveillance system, but others, e.g. polyomaviruses like SV40, activate it and somehow harness it to facilitate robust replication of viral progeny. We have sought to determine how SV40 induces and deploys host DNA damage signaling in infected cells to promote viral chromosome replication. Here we present evidence that, like host DNA, replicating viral DNA suffers damage that activates surveillance and repair pathways. Unlike host replication, viral DNA replication persists despite damage signaling, allowing defective replication products to accumulate. In the presence of host DNA damage signaling, these defective viral products attract proteins of the host damage surveillance network that correct the defects, thus maximizing viral propagation.
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影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
5.4
作者：
Dahl, J;You, J;Benjamin, TL
通讯作者：
Benjamin, TL
DOI：
10.1073/pnas.1211525109
发表时间：
2012-08-14
影响因子：
11.1
作者：
Ilves, Ivar;Tamberg, Nele;Botchan, Michael R.
通讯作者：
Botchan, Michael R.
影响因子：
9.8
作者：
Casper, AM;Durkin, SG;Glover, TW
通讯作者：
Glover, TW